rs776187492

chr2-151591368-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164507.2(NEB):c.14914T>A(p.Ser4972Thr) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0015 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.61

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010239273).
• BP6: Variant 2-151591368-A-T is Benign according to our data. Variant chr2-151591368-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 257748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151591368-A-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.14914T>A	p.Ser4972Thr	missense_variant	96/182	ENST00000427231.7
NEB	NM_001164508.2	c.14914T>A	p.Ser4972Thr	missense_variant	96/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.14914T>A	p.Ser4972Thr	missense_variant	96/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.14914T>A	p.Ser4972Thr	missense_variant	96/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11602-15014T>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 208 AN: 152152 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00326

Gnomad SAS AF: 0.0214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000955

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00147 AC: 2048 AN: 1397180 Hom.: 11 Cov.: 33 AF XY: 0.00197 AC XY: 1357 AN XY: 689042

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00246

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.000344

Gnomad4 NFE exome AF: 0.000239

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00137 AC: 208 AN: 152270 Hom.: 0 Cov.: 30 AF XY: 0.00168 AC XY: 125 AN XY: 74434

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00327

Gnomad4 SAS AF: 0.0214

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00106 Hom.: 0

ExAC AF: 0.00262 AC: 185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Benign	0.95
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;T;T;.;.
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.34	N;.;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.33	T;.;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.46
MutPred		0.43		Loss of disorder (P = 0.0986);Loss of disorder (P = 0.0986);Loss of disorder (P = 0.0986);Loss of disorder (P = 0.0986);Loss of disorder (P = 0.0986);
MVP		0.67
MPC		0.21
ClinPred		0.025	T
GERP RS		3.2
gMVP		0.0052

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776187492; hg19: chr2-152447882; COSMIC: COSV51471988;